endpoints resucitacion.pdf

End Points of Sepsis Resuscitation John C. Greenwood,

MD

a,b,

*, Clinton J. Orloski,

MD

c

KEYWORDS  Resuscitation end points  Resuscitation  Sepsis  Septic shock  Critical care  Lactate  Capillary refill time KEY POINTS  Using the CVP as an initial resuscitation end point and estimate of preload adequacy in the patient with sepsis is fraught with error; dynamic indices are preferred.  Peripheral vasoactive infusions are acceptable in the short-term while assessing response to additional fluid challenges or central venous access is being secured.  Targeting a supranormal cardiac index to provide higher levels of tissue oxygen delivery has not been shown to improve clinical outcomes.  A peripheral lactate level of greater than 2 mmol/L is now recommended as a threshold that indicates sepsis-induced organ dysfunction.  Serial assessment of capillary refill time, with normalization at 6 hours, is independently associated with successful resuscitation when compared with traditional microcirculatory resuscitation targets, such as ScvO2, Pcv-aCO2 gap, and lactate normalization.

INTRODUCTION

Sepsis is defined as a syndrome of life-threatening organ dysfunction caused by a dysregulated host response to infection.1 If unrecognized and left untreated, patients with sepsis can quickly deteriorate, develop multisystem organ failure, and die. Physiologic changes that occur include peripheral vasodilation, myocardial depression, systemic microcapillary injury, coagulopathy, and end-organ malperfusion.2–4 Resuscitation goals for the patient with sepsis and septic shock attempt to return the patient to a physiologic state that promotes adequate organ perfusion along Funding Sources: Nothing to disclose. Conflict of Interest: Nothing to disclose. a Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Ground Ravdin, Philadelphia, PA 19014, USA; b Department of Anesthesiology & Critical Care, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Ground Ravdin, Philadelphia, PA 19014, USA; c Department of Emergency Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Ground Ravdin, Philadelphia, PA 19104, USA * Corresponding author. Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Ground Ravdin, Philadelphia, PA 19014. E-mail address: [email protected] Emerg Med Clin N Am 35 (2017) 93–107 http://dx.doi.org/10.1016/j.emc.2016.09.001 0733-8627/17/ª 2016 Elsevier Inc. All rights reserved.

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with matching metabolic supply and demand. Ideal resuscitation end points should assess the adequacy of tissue oxygen delivery (DO2), oxygen consumption (VO2), and should be quantifiable and reproducible. Despite years of research, a single resuscitation end point to assess the adequacy of sepsis resuscitation has yet to be found. As a result, the clinician must rely on multiple end points to determine the patient’s overall response to therapy. This article discusses the roles and limitations of currently recommended resuscitation end points, and identifies novel resuscitation targets that may help guide therapeutic interventions in the patient with sepsis and septic shock. CURRENT RESUSCITATION TARGETS FOR SEPSIS AND SEPTIC SHOCK

To address the many physiologic derangements that occur in patients with sepsis, and also provide objective resuscitation triggers to guide clinical intervention, several organizations have developed treatment “bundles” that include hemodynamic and physiologic markers used to assess physiologic status of the patient with sepsis. The Surviving Sepsis Campaign has become one of the international leaders of bundled or protocolized sepsis care, and has made a significant impact on the mortality attributed to sepsis and septic shock.5,6 The most recent iteration of the Surviving Sepsis Campaign guidelines focuses on several resuscitation targets identified by the original early goal-directed therapy (EGDT) protocol, with an emphasis on macrocirculatory and microcirculatory end points (Box 1).7,8 Protocolized sepsis resuscitation is not without controversy. To test the current paradigm of sepsis care, three separate multicenter randomized control trials compared the EGDT protocol with contemporary care and found no difference in clinical outcomes.9–11 The results of ProCESS, ARISE, and ProMISe trials have generated a significant debate about the value of a “one size fits all” approach in sepsis resuscitation.5,12 MACROCIRCULATORY RESUSCITATION END POINTS

In the initial phase of sepsis resuscitation, it is important to first target macrocirculatory resuscitation end points. Macrocirculatory targets can usually be measured rapidly at the bedside and address intravascular volume status, mean arterial pressure (MAP), and cardiac output. Early recognition of macrocirculatory derangements often prevents early cardiovascular collapse and is a good initial step in the resuscitation of the patient with sepsis or septic shock.

Box 1 Surviving Sepsis Campaign resuscitation goals within the first 6 hours 1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined as hypotension persisting after initial fluid challenge or blood lactate concentration 4 mmol/L). a. Central venous pressure i. Spontaneously breathing patients: 8 to 12 mm Hg ii. Mechanically ventilated patients: 12 to 15 mm Hg b. Mean arterial pressure 65 mm Hg c. Urine output 0.5 mL/kg/h d. Central venous oxygen saturation 70% or mixed venous oxygen saturation 65% 2. In patients with elevated lactate levels targeting resuscitation to normalize lactate as rapidly as possible.

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Intravascular Volume Status

Intravenous fluid administration is a cornerstone of sepsis resuscitation. Rapid fluid administration in the setting of hypovolemia or significant vasoplegia often restores visceral blood flow and tissue DO2 by improving cardiac output and consequently MAP. An initial, empiric fluid challenge of 500 mL of intravenous crystalloid solution up to a maximum of 30 mL/kg is a reasonable first approach to improve a patient’s hemodynamic status.9,10,13 Additional crystalloid administration should be driven by objective clinical findings that suggest additional fluid therapy would improve cardiac output and organ perfusion. The utility of intravascular fluid resuscitation is limited by the amount of time resuscitative fluids remain within the intravascular space.14,15 Overresuscitation can lead to significant downstream complications, which include significant third spacing and reduced delivery of oxygen to end-organ tissues.16 Static measures of volume responsiveness are defined as pressure or volumetric hemodynamic indices that are measured at a single point in time for preload assessment (ie, central venous pressure [CVP], pulmonary artery occlusion pressure). Static measures of preload assessment have largely been replaced with dynamic indices that take advantage of heart-lung interactions to predict volume responsiveness. Stroke volume variation, pulse pressure variation, and inferior vena cava variability all have a better positive predictive value, sensitivity, and specificity than static measures.17–19 Direct measurement tests of volume responsiveness include the endexpiratory occlusion test and passive leg raise and may be preferred over dynamic measures, because these tests can be used in patients who are spontaneously breathing, have arrhythmias, and can help avoid unnecessary fluid administration.20–22 Central Venous Pressure

The CVP is a static, barometric measurement that requires a central venous catheter for measurement, and describes the pressure generated by the intravascular blood volume present in the superior vena cava. It is a directly measured estimate of right atrial and right ventricular end-diastolic pressure. Traditionally, the CVP has been used as an estimate of intravascular volume status and a predictor of volume responsiveness. In a healthy, nonintubated patient, the CVP is approximately 2 mm Hg to 4 mm Hg. Current recommendations suggest that CVP in the patient with sepsis should be increased with intravenous fluids to a goal of 8 mm Hg to 12 mm Hg in spontaneously breathing patients, or 12 mm Hg to 15 mm Hg in mechanically ventilated patients, to ensure adequate preload to optimize cardiac output.23 Unfortunately, several patientrelated and physiologic changes can impact the CVP and make it an unreliable tool for preload optimization.24–26 Even traditional teaching, that a low CVP is often a reliable measure of volume responsiveness, has been found to have a positive predictive value of only 47% in patients with sepsis.24 Using the CVP as an initial resuscitation target and estimate of preload adequacy is fraught with error, because there are several confounding factors that can impact the CVP outside of intravascular volume status (Box 2). In general, initial fluid resuscitation should be actively guided by dynamic measures of volume responsiveness to improve cardiac output and end-organ perfusion. Mean Arterial Pressure

One of the hallmark hemodynamic derangements that can lead to organ dysfunction in sepsis is hypotension. Diagnostic criteria for sepsis-related arterial hypotension

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Box 2 Potential factors impacting central venous pressure 1. Central venous blood volume a. Venous return/cardiac output b. Total blood volume c. Regional vascular tone 2. Thoracic, cardiac, and vascular compliance a. Pulmonary hypertension b. Right ventricular compliance, diastolic dysfunction c. Pericardial disease d. Tamponade 3. Valvular disease a. Tricuspid stenosis b. Tricuspid regurgitation 4. Cardiac rhythm a. Junctional rhythm b. Atrial fibrillation c. Nonsinus rhythm 5. Intrathoracic pressure a. Spontaneous or noncontrolled respiration b. Intermittent positive pressure ventilation c. Positive end-expiratory pressure 6. Reference level of pressure transducer and patient positioning

include a systolic blood pressure of less than 100 mm Hg (recently increased from 90 mm Hg),1 MAP less than 70 mm Hg, or an systolic blood pressure decrease of more than 40 mm Hg in adults or less than two standard deviations below normal for a given age.8 An initial MAP target of 65 mm Hg during the acute phases of sepsis resuscitation is generally recommended, with individualized MAP titration after stabilization.8 The threshold target of 65 mm Hg is largely based off of a small set of retrospective, prospective, and observational studies that found adequate perfusion measures and a reduction in associated mortality with MAP threshold of 65 mm Hg.27,28 Targeting a higher MAP has not been found to reduce organ dysfunction or improve global outcomes, but may improve microvascular perfusion on an individualized basis.28,29 In 2014, the multicenter Sepsis and Mean Arterial Pressure (SEPSISPAM) randomized controlled trial was conducted to look specifically at outcomes related to higher MAP compared with standard goals (target of 80–85 mm Hg vs 65–70 mm Hg) and found no significant difference in 28- or 90-day mortality. A predefined subset of patients with chronic hypertension required less renal-replacement therapy than those in the low-target group.30 The SEPSISPAM trial reinforced the need for clinicians to recognize the potential benefit of individualized blood pressure titration, especially in patients with chronic disease. Interventions to achieve a MAP greater than 65 mm Hg in the patient presenting with sepsis or septic shock should begin with an assessment of intravascular volume status to determine the clinical utility of intravascular fluid loading to improve cardiac output and mean blood pressure. Once adequate intravascular volume status has been achieved, early administration of vasopressors should be initiated if the patient remains hypotensive. Norepinephrine is generally the initial vasopressor of choice in septic shock, starting at a dose of 0.05 mg/kg/min.31

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Rapid initiation of vasopressor therapy in the setting of fluid-refractory shock is a time-critical intervention. Delayed initiation of vasopressor therapy can lead to excessive fluid resuscitation and increased morbidity and mortality. A mortality increase of 5.3% has been estimated to occur for every 1-hour delay in vasopressor initiation during the first 6 hours of septic shock.32 In patients who are not responding to escalating doses of norepinephrine, early administration of adjunctive therapies should also be considered. The addition of stress-dose hydrocortisone, along with vasopressinreplacement therapy, or an epinephrine infusion is generally recommended as second-line agents. Traditionally, vasoactive administration required a central venous catheter out of fear of complications related to extravasation and soft tissue necrosis; however, more recent literature suggests that this complication is rare.33,34 Delays in vasoactive support are avoided safely by administering vasopressors through a proximal, large-bore peripheral intravenous access line. Peripheral vasoactive infusions are acceptable in the short-term while assessing response to additional fluid challenges or central venous access is being secured. Cardiac Output and Cardiac Index

The early phase of septic shock is often characterized by a low systemic vascular resistance and a high cardiac output or cardiac index. Most patients with sepsis present with “warm shock,” a term used to describe a hypotensive patient with flushed skin, bounding peripheral pulse, yet a significant mismatch between DO2 and metabolic demand. The patient with sepsis with “cold shock,” presenting with poor peripheral perfusion and cool extremities, suggesting poor cardiac output, is less common. An abnormally low cardiac output presenting as cold shock is associated with inadequate volume resuscitation, but can occur in the setting of acute sepsis-induced cardiac dysfunction or during the late phases of septic shock.35 Sepsis-induced cardiac dysfunction is a well-described phenomenon that leads to a reduction in left ventricular stroke volume and impaired myocardial performance. The incidence of myocardial depression is estimated to occur in up to 60% of patients with septic shock.3 The exact cause of cardiac dysfunction in sepsis is unclear, but is believed to be a multifactorial cellular insult on myocardial tissues that includes decreased b-adrenergic receptor sensitivity, calcium sensitivity, increased nitric oxide production, mitochondrial dysfunction, and cell death.35 Assessing cardiac output in patients with septic shock is performed by several minimally invasive and noninvasive methods, including pulse wave contour analysis devices, such as the LiDCO (LiDCO Ltd, London, UK); PiCCO (Pulsion Maquet, Munich, Germany); FloTrac/Vigileo system (Edwards Lifesciences Corp, Irvine, CA); bioreactance measurement systems, such as the NICOM (Cheetah Medical, Boston, MA); or bedside echocardiography. The routine use of invasive cardiac output monitoring devices, such as the pulmonary artery catheter, has been associated with increased patient risks without significant benefit, and as a result their use has fallen out of favor.36 Despite the increased recognition of sepsis-induced cardiac dysfunction, not all patients with a reduced left ventricular ejection fraction require inotropic therapy. Using equipment that is generally available in most acute care settings, a general assessment of cardiac function is acquired with minimal training. Calculating a patient’s cardiac output is performed by obtaining two, simple echocardiographic measurements (Fig. 1). Stroke volume is estimated by calculating the product of the patient’s left ventricular outflow tract (LVOT) velocity-time integral and the patient’s aortic valve area measured with bedside echocardiography. The LVOT velocity-time integral is

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Fig. 1. (A) Measurement of the left ventricular outflow tract (LVOT) diameter during systole, which can be used to estimate the aortic valve area using transthoracic echocardiography (TTE). (B) Measurement of the LVOT velocity time integral (VTI) in the apical five-chamber view.

measured in the apical five-chamber view using the pulsed-wave Doppler function, with the marker placed within the LVOT. The aortic valve area is estimated by measuring the diameter of the patient’s LVOT approximately 1 cm below the aortic valve in the parasternal long axis. Multiplying the patient’s estimated stroke volume

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by their current heart rate yields the cardiac output. Cardiac index is calculated by dividing the patient’s cardiac output by their body surface area. Note that cardiac dysrhythmias and inaccurate LVOT diameter measurements can significantly impact the accuracy of cardiac output measurement. After adequate volume resuscitation and initiation of vasopressor support, if a patient continues to have poor cardiac output (cardiac index of <2.2 L/min/m2) with evidence of poor perfusion, it is reasonable to add inotropic therapy. Dobutamine is recommended as the first-line inotropic infusion, at a starting dose of 2.5 mg/kg/min in patients with adequate ventricular filling and MAP.8 Alternatively, epinephrine may provide adequate inotropic support if given at lower infusion doses (up to 0.1 mg/kg/min) without the vasodilatory effects caused by dobutamine’s b2 activity.37 If choosing epinephrine, it is important to recognize that the ability to monitor lactate clearance may be negatively impacted because of increased aerobic glycolysis and lactate production.38 In patients with adequate volume resuscitation and an escalating norepinephrine requirement, the decision algorithm in Fig. 2 may be considered. A specific cardiac index goal is not currently recommended; however, a reasonable approach is to initially target a cardiac index of 2.2 L/min/m2 to 2.5 L/min/m2. Targeting a supranormal cardiac index to provide higher levels of tissue DO2 has not been shown to improve clinical outcomes.39 MICROCIRCULATORY RESUSCITATION END POINTS

After achieving the macrocirculatory targets during the initial phase of sepsis resuscitation it is important to assess whether these end points have established adequate organ perfusion. Some patients who achieved macrocirculatory thresholds may

Fig. 2. Potential decision algorithm for second-line vasoactive therapy in the management of septic shock. a There is no maximum dose for norepinephrine or epinephrine. CI, cardiac index; ScvO2, central venous oxygen saturation; TTE, transthoracic echocardiography.

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require continued resuscitative efforts to reverse their occult, or “cryptic,” shock, whereas others may not need to be maintained at the established macrocirculatory thresholds.40,41 The next step of resuscitation is to assess the adequacy of organ perfusion by way of microcirculatory resuscitation targets. Microcirculation is defined by a network of arterioles, capillaries, and postcapillary venules that are responsible for the delivery of red blood cells and plasma to organs so that cellular exchange of oxygen, carbon dioxide, nutrients, cytokines, and metabolic waste removal can occur. Sepsis-induced inflammation, coagulopathy, leukocyte dysfunction, and overproduction of nitric oxide can lead to significant changes in microvascular blood flow, cytotoxic stress, and an imbalance between oxygen delivery and demand.2,42–44 There are several clinical and laboratory values used to assess microvascular perfusion, the most common being peripheral lactate and central venous oxygen saturation (ScvO2). Clinical assessment of microcirculation can also be performed by way of capillary refill time (CRT), and in some cases urine output. Lactate

Peripheral lactate, also referred to as lactic acid, has become one of the most widely used biomarkers to diagnose sepsis-induced organ dysfunction. It is drawn from a peripheral intravenous line and has been shown to correlate with venous, arterial, and capillary blood samples.45,46 Traditionally, a venous lactate greater than or equal to 4 mmol/L has been used as an initial screen for sepsis-induced organ dysfunction, but more recently, a lactate threshold of 2 mmol/L has been recommended.1,8,47–49 In a healthy individual at rest, peripheral lactate concentrations are usually between 0.5 mmol/L and 2 mmol/L. During periods of physiologic stress, lactate generation often occurs. An elevated lactate in the patient with sepsis has been associated with a significantly increased risk of mortality.50 Unfortunately, a rise in lactate is not always associated with obvious hemodynamic abnormalities.51 “Cryptic shock” is a term used to describe the patient with apparently normal vital signs but a significant elevation in peripheral lactate. Despite reassuring vital signs, the patient with sepsis with cryptic shock has a mortality risk similar to those with overt shock, and should receive careful resuscitation.41 A significant debate regarding the utility of lactate as a resuscitation end point remains in the academic community.52 Traditional theory is that increased lactate production occurs in sepsis as a result of global tissue hypoxia, where oxygen supply (DO2) fails to meet oxygen demand (VO2). The resulting DO2/VO2 mismatch leads to increased anaerobic metabolism and a rise in the patient’s lactate level. Unfortunately, this simplistic explanation for a rise in lactate fails to consider multiple other physiologic and nonphysiologic contributors to an elevated lactate (Box 3). Despite the nuances of lactate generation and metabolism, the use of lactate as a marker of microcirculatory perfusion adequacy and resuscitation response seems to be the best option to date, but clinicians should be aware of its limitations and potential confounders.53,54 Mixed and Central Venous Oxygen Saturation

Achieving adequate tissue oxygenation along with avoiding tissue dysoxia is essential to prevent cell injury, oxygen debt, organ dysfunction, and death. Both mixed venous oxygen saturation (SvO2) and ScvO2 have been proposed as important resuscitation targets in the patient with sepsis, because they can be used to estimate a global balance of cellular oxygen delivery and demand. A low ScvO2 (<70%) indicates an

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Box 3 Causes of lactate elevation in sepsis 1. Anaerobic glycolysis: caused by tissue hypoxemia 2. Aerobic glycolysis: increased stress response, endogenous catecholamine release, and stimulation of b2 receptors 3. Mitochondrial dysfunction: limited pyruvate metabolism 4. Acute lung injury: metabolic adaptation to inflammatory mediators 5. Decreased lactate clearance a. Liver failure or dysfunction b. Renal failure or dysfunction 6. Drugs and toxins: patient medications (eg, metformin), vasoactive agents, toxic ingestions (eg, ethanol) 7. Other causes: metabolic alkalosis

inadequate DO2 to tissues, an increased extraction at the cellular level (VO2), or a combination of these two factors. To obtain an SvO2/ScvO2 measurement, the sampling location is an important consideration. A true SvO2 measurement requires a pulmonary artery catheter, and an ScvO2 measurement must be obtained through a central venous catheter where the tip is appropriately placed at the junction of the superior vena cava and right atrium. Femoral-based ScvO2 is not a reliable substitute for an ScvO2 measurement taken from the superior vena cava–right atrium junction.55 If measured from the appropriate location, an ScvO2 between 70% and 89% would suggest an adequate VO2/DO2 balance, and seems to correlate well with a normal SvO2 value between 60% and 70%.56 A supranormal ScvO2 value equal or greater than 90% suggests poor oxygen utilization, tissue dysoxia, or significant microcirculatory shunting and is associated with a high mortality.57 Since the original EGDT trial was published in 2001, several studies have examined the use of peripheral lactate versus ScvO2 optimization and have found no difference in patient-centered outcomes.9,10,13,48 Outside of the EGDT trial, the incidence of an abnormally low ScvO2 in patients with sepsis that present to the emergency department and at intensive care unit admission seems to be low.9,58 Currently, the routine use of ScvO2 should not be incorporated into current sepsis resuscitation protocols. However, there may be a role for ScvO2 monitoring in specific sepsis phenotypes (eg, sepsis-induced cardiac dysfunction) and future research should attempt to determine its utility.59 Central Venous-Arterial CO2 Gradient

The inability of a normal or high ScvO2 to regularly determine adequate organ perfusion has led clinicians to look for other markers of tissue hypoxia and metabolic disequilibrium. The venous-to-arterial carbon dioxide gradient has been proposed as one of these adjunctive tests to determine if the patient has achieved adequate cardiac output along with adequate microcirculatory flow and perfusion. It is calculated by subtracting the arterial PCO2 from the central venous PCO2 (ScvO2). The Pcv-aCO2 gap has become more popular in recent years as a resuscitation end point largely because CO2 is more soluble than O2 in the blood and may be able to more accurately detect microcirculatory dysfunction, even in the setting of

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heterogeneous or poor microcirculatory flow. In multiple studies, a Pcv-aCO2 gap that is less than 6 mm Hg has been found to be associated with a higher cardiac index, better lactate clearance, and improved microcirculatory perfusion.60–62 Conversely, a Pcv-aCO2 gap that is greater than 6 mm Hg can reliably reflect critical hypoperfusion and the need for further resuscitation.63 CLINICAL ASSESSMENTS OF PERFUSION

Interventions during the resuscitation of the patient with sepsis or shock should be performed in tandem with regular reassessment of clinical response. Laboratory testing is often relied on to determine improvements in end-organ perfusion, but in some cases advanced laboratory testing may not be readily available. It is important for the clinician to also have an array bedside tools that can help assess resuscitation adequacy if necessary. Capillary Refill Time

The assessment of CRT in the patient with sepsis may seem counterintuitive, because pathophysiologic derangements often lead to peripheral vasodilation resulting in warm, flushed extremities. However, emerging literature suggests CRT may be a valuable bedside tool to assess the adequacy of not only regional, but also global tissue perfusion during the resuscitation phase of septic shock.64 CRT is a simple, low cost, and reliable evaluation of microvascular perfusion that is performed rapidly at the bedside.65,66 It is defined as the duration of time needed for the patient’s fingertip to regain color after direct pressure is applied to cause blanching. In a healthy patient, the CRT should be less than 3.5 seconds. Skin temperature, ambient room temperature, age, and vasoactive medications can significantly impact CRT and should be considered during each assessment. In the patient with sepsis, assuming the patient’s extremities are normothermic, delayed CRT of more than 5 seconds suggests abnormal microcirculatory flow and need for further intervention (Fig. 3).67 Serial assessment of CRT with normalization at 6 hours is independently associated with successful resuscitation when compared against traditional resuscitation targets, such as ScvO2, Pcv-aCO2 gap, and lactate normalization.68 In the postresuscitation phase of critical illness, delayed CRT may also be a predictor of worsening organ failure and shock.69 Urine Output and Oliguria

Acute kidney injury (AKI) is defined by a relative increase in serum creatinine, reduction in glomerular filtration rate, or reduced urine output and is the most common organ dysfunction associated with sepsis in critically ill patients.70,71 Traditional resuscitation

Fig. 3. (A) Normal capillary refill time of less than 3.5 seconds. (B) Abnormal capillary refill time of greater than 5 seconds.

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end points, including those from the most recent Surviving Sepsis Campaign, recommend a patient’s urine output be greater than 0.5 mL/kg/min to suggest adequate renal perfusion in the early stages of resuscitation.8 Urine output is largely a function of glomerular filtration, tubular secretion, and reabsorption. Glomerular filtration is particularly dependent on renal blood flow (RBF), which is dependent on circulating blood volume, cardiac output, and renal perfusion pressure. In a healthy state, RBF is stable over a wide range of MAPs because of local autoregulation.72 In periods of shock, or specifically the patient with sepsis, mechanisms responsible for blood flow autoregulation become impaired. Unfortunately, the pathophysiologic process leading to oliguria and AKI is far more complex than addressing macrocirculatory resuscitation targets alone. Clinicians have attempted to pharmacologically increase urine output in high-risk patients by increasing RBF with low-dose dopamine and decrease tubular VO2 with diuretics, but neither of these interventions has been shown to reduce the incidence of AKI, and is not recommended.73,74 During the resuscitation phase of sepsis and shock, interventions to improve urine output should focus on intravascular fluid optimization, achieving macrohemodynamic goals, and avoiding unnecessary nephrotoxic agents. Choice of intravenous crystalloid, at least for the first 2 to 3 L, does not seem to have an impact on the development of AKI.75 For large-volume resuscitations, it is reasonable to switch to a balanced crystalloid solution (eg, lactated Ringer) to avoid the development of a worsening hyperchloremic metabolic acidosis, which has been associated with the development of AKI and need for renal-replacement therapy.76 SUMMARY

Early, aggressive resuscitation of the acutely ill patient with sepsis and septic shock is a fundamental concept in emergency medicine and critical care. Initial resuscitative efforts should focus on achieving established macrocirculatory goals, including adequate intravascular volume status, MAP, and cardiac output. The patient’s global response to resuscitative interventions is assessed with the evaluation of microcirculatory end points including peripheral lactate, ScvO2, and carbon dioxide gradients (Pcv-aCO2). Further attention to clinical findings, such as CRT and urine output, may help the clinician recognize subtle microvascular perfusion abnormalities, but have important limitations to consider. REFERENCES

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